Epigenetic Remodeling Hydrogel Patches for Multidrug‐Resistant Triple‐Negative Breast Cancer

• Published in: Advanced materials (Weinheim) 2021-05, Vol.33 (18), p.e2100949-n/a
• Main Authors: Ji, Xiaoyuan, Guo, Daoxia, Ma, Jia, Yin, Min, Yu, Yun, Liu, Chang, Zhou, Yanfeng, Sun, Jinli, Li, Qian, Chen, Nan, Fan, Chunhai, Song, Haiyun
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Breast cancer; Cell Line, Tumor; Drug Resistance, Multiple - drug effects; Drug Resistance, Neoplasm - drug effects; Epigenesis, Genetic - drug effects; epigenetic remodeling hydrogel patches; Epigenetics; Female; Histone Demethylases - antagonists & inhibitors; Histone Demethylases - genetics; Histone Demethylases - metabolism; Humans; Hydrogels; Hydrogels - chemistry; innate immunity; Lysine; Metastasis; Mice; multidrug resistance; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - metabolism; Patches (structures); Reactive Oxygen Species - metabolism; Triple Negative Breast Neoplasms - drug therapy; Triple Negative Breast Neoplasms - pathology; Tumor Microenvironment - drug effects; Tumors; tumor‐initiating cells
• ISSN: 0935-9648; 1521-4095; 1521-4095
• DOI: 10.1002/adma.202100949

The induced expansion of tumor‐initiating cells (T‐ICs) upon repeated exposure of tumors to chemotherapeutic drugs forms a major cause for chemoresistance and cancer metastasis. Here, a tumor‐microenvironment‐responsive hydrogel patch is designed to modulate the plasticity of T‐ICs in triple‐negative breast cancer (TNBC), which is insensitive to hormone‐ and HER2‐targeting. The on‐site formation of the hydrogel network patches tumors in a chemoresistant TNBC murine model and senses intratumoral reactive oxygen species for linker cleavage and payload release. Patch‐mediated inhibition of the histone demethylase lysine‐specific demethylase 1 (LSD1) epigenetically regulates the switch of T‐ICs from self‐renewal to differentiation, rehabilitating their chemosensitivity. Moreover, the hydrogel patch enhances tumor immunogenicity and increases T‐cell infiltration via epigenetic activation of innate immunity. A single‐dose of the hydrogel patch harboring LSD1 inhibitor and chemotherapy agent efficiently suppresses tumor growth, postsurgical relapse, and metastasis. The superior efficacy against multidrug resistance further reveals the broad applicability of epigenetic remodeling hydrogel patches. Epi‐gel provides chemosensitivity recovery and immune activation via simultaneous remodeling of tumor‐initiating cells (T‐IC) stemness and innate immune response. A single dose of epi‐gel pools the advantages of epigenetic therapy, immunotherapy, and chemotherapy in the treatment of multidrug‐resistant triple‐negative breast cancer (TNBC), achieving superior therapeutic outcomes compared to conventional drug delivery.